PROFESSOR MARK PALLEN

The Phylogenomics of Cancer

Charles Darwin 1809-1882

Shrewsbury; Edinburgh; Cambridge (1809-31)

Beagle voyage (1831-36)London (1836-42) Down House (1842-1882)

Geology; Zoology; Barnacles Voyage of the Beagle, 1839

Evolution Origin of Species, 1859 (“one

long argument”). Descent of Man, 1871

Natural SelectionNatural Selection

Fecundity of NatureStruggle for ExistenceFecundity of Nature

Struggle for Existence

Darwin’s Theory of Evolution

Newton’s law-governed

universe

Hutton and Lyell’s deep time and

uniformitarianism

The Beagle voyageFossils and biogeography

Family tradition of religious dissent

and r/evolutionary ideas

Paley’s Natural Theology

Humboldt’s adventures in natural history

Malthus Essay on Population

Scottish enlightenmentSmith’s Invisible Hand

Wallace’s letter

Mutability of SpeciesVestigial features

Mutability of SpeciesVestigial features

Non-Progressive Branching Evolution

Non-Progressive Branching Evolution

Evolutionary GradualismEvolution of complex organs

Nature rich in variety, poor in innovation

Evolutionary GradualismEvolution of complex organs

Nature rich in variety, poor in innovation

Population ThinkingBlurred boundaries

between species and varieties

Population ThinkingBlurred boundaries

between species and varieties

ExtinctionImperfection of fossil record

ExtinctionImperfection of fossil record

VariationReproduction

Selection

VariationReproduction

Selection

Sexual SelectionSexual Selection

Principle of divergenceTaxonomy as Genealogy

Tree of Life: Common DescentHomology equals similarity

from common ancestry

Principle of divergenceTaxonomy as Genealogy

Tree of Life: Common DescentHomology equals similarity

from common ancestry

BiogeographyGeography reflects genealogy

Dispersal and Adaptive Radiation

BiogeographyGeography reflects genealogy

Dispersal and Adaptive Radiation

Natural Selection

Non-Progressive Branching Evolution

Evolutionary Gradualism

Natural Selection…

“Owing to this struggle for life, any variation, however slight and from whatever cause proceeding, if it be in any degree profitable to an individual of any species, in its infinitely complex relations to other organic beings and to external nature, will tend to the preservation of that individual, and will generally be inherited by its offspring. The offspring, also, will thus have a better chance of surviving, for, of the many individuals of any species which are periodically born, but a small number can survive.

I have called this principle, by which each slight variation, if useful, is preserved, by the term of Natural Selection, in order to mark its relation to man's power of selection. We have seen that man by selection can certainly produce great results, and can adapt organic beings to his own uses, through the accumulation of slight but useful variations, given to him by the hand of Nature. But Natural Selection, as we shall hereafter see, is a power incessantly ready for action, and is as immeasurably superior to man's feeble efforts, as the works of Nature are to those of Art.”On the Origin of Species, 1859

Natural Selection… without genetics

“Our ignorance of the laws of variation is profound. Not in one case out of a hundred can we pretend to assign any reason why this or that part differs, more or less, from the same part in the parents.”

From Mendel to the Modern Synthesis

Mendel’s experiments on peas in 1860s Rediscovered in 1900s

Soma/germ-line distinction (Weismann) Chromosomes; mutations Twilight of Darwinism; persistence of “Lamarckianism” 1940s:

“Modern Synthesis” of Evolution and Genetics ‘Mendel meets Darwin’

Spectrum of genome evolution

Homo neanderthal

ensis

Extinct hominins

Living primates

Homo sapiens

Cancer evolution

What is Cancer?

Cancers or malignant neoplasms occur in multicellular organisms when a group of cells displays uncontrolled growth, invasion ± metastasis

By contrast benign tumours are self-limited and do not invade or metastasize

Cancer cells are cheaters on the contract between genomically identical cells to create multicellular bodies to propagate the germ line

Six hallmarks of cancer

1. self-sufficiency of cells in signals controlling growth

2. loss of sensitivity to antigrowth signals3. evasion of apoptosis via mutation or loss of

gatekeeper genes4. development of limitless replicative potential,

usually via the expression of telomerase5. sustained angiogenesis, whereby the blood

supply to a tumor is augmented6. tissue invasion and metastasis

Simple views of cancer

Nowell, 1976

Nowell, 1976

Cancer as an evolutionary process

Descent with Modification

Branching Evolution

Natural Selection in Cancer

Three prerequisites are necessary and sufficient for evolution by natural selection :1. Individual variations exist in the population2. These variations are heritable3. Variations in individuals lead to differential survival

and reproduction

Natural Selection in Cancer

Cancer composed of billions of malignant cells descended from single progenitor all carry somatic mutations present in founder cell additional mutations acquired by generations of daughter

cells during tumour progression genomic instability fuels genetic intra-tumour heterogeneity

Diversification into subclones, which compete for resources, such as oxygen, vascular supply, growth signals and vary in growth rate, invasiveness etc

Natural selection drives selective sweeps and adaptation to local micro-environments

Artificial Selection in Cancer

Development of resistance to cancer chemotherapeutics governed by Darwinian natural selection, an inevitable consequence of genetic diversity and selective pressure.

Artificial Selection in Cancer

Cancer stem cells with genetic instability: the best vehicle with the best engine for cancer E Lagasse

Evolution of the Cancer

Genome

~1% of our coding genes, >350 genes, can, as mutants, contribute to cancer clone evolution

Driver mutationsDriver mutations Passenger mutationsPassenger mutations

Contribute to oncogenesis; provide growth advantage; selected for in micro-niche

Occur in oncogenes (gain of

function mutations) or tumour-suppressor genes

(loss of function mutations)

Neutral mutationsCarried along for the

ride somatic mutations without

functional consequences often occur during cell division

PLUS huge increase in mutation rate with loss of genome repair mechanisms

Passengers and Drivers

Why Cancer?

Different types of causation within a causal chain Epidemiologists say cigarette tar causes lung cancer Molecular biologists say gene mutations cause lung

cancer

Mechanistic versus evolutionary causation Evolutionary or Darwinian medicine

Why is cancer common especially in humans? one in three lifetime risk

Why Cancer?

cancer as reversion to unicellular selfishness multicellularity requires the social

cohesion of cells and the severe prohibition of clonal escape

cancer as intrinsic fallibility that escalates with increasing complexity and longevity intrinsic mutability and recombination

capacity of DNA incomplete fidelity of repair

Why Cancer?

Disposable soma flaws or trade-offs apparent only in old age

tolerated so long as they do not impact deleteriously on reproductive fitness

Cellular attributes required for cell cycle, viviparity and embryogenesis available for co-option by malignant cells e.g. immunological tolerance; motility, chemotaxis,

migration and invasiveness

Stem cells retain intrinsic competence for transient, selfish replication

Why Cancer?

Stone age genome versus 21st century lifestyle pale skin provides more vitamin D, but leads to cancer

in e.g. white Australians with sun exposure breast and ovarian cancer arise from mismatch

between hunter-gatherer reproductive physiology and modern reproductive and breast-feeding choices

prostate cancer as sides effect of large prostate driven by need for sperm production matched to non-seasonal oestrus

Why Cancer?

No eyes to the future…Darwinian natural selection operates on a

“what works best today” basis. selects genetic variants from the limited

options available that best fit the prevailing conditions.

winners today can become losers tomorrow: cancer cells kill their host!

Genome evolution in Chimps, Humans, Cancers…

Genome evolution in Chimps, Humans, Cancers…

Structural alterations linked to single-nucleotide changes across different time scales in somatic- and germ-cell lineages at species level in personal genomes in human cancer cell populations

Proposed explanation low fidelity of non-replicative error-prone repair

polymerases, used during insertion or deletion, results in break-repair-induced single-nucleotide mutations in the vicinity of structural alteration

Cancer and the birth and death of species

Henrietta Lacks 1920 -1951

African–American woman Born in Roanoke, Virginia married her first cousin,

David "Day" Lacks Moved to Baltimore County,

Maryland when David started working in shipyard

Five children: Lawrence, Elsie, David "Sonny" Jr., Deborah, and Joseph (born 1950; later changed name to Zakariyya Bari Abdul Rahman).

Henrietta Lacks 1920 -1951

Feb 1951, Lacks visits Johns Hopkins with painful lump in her cervix and bloody vaginal discharge After biopsy, diagnosed with unusually

aggressive cervical cancer Eight days later, Dr. George Gey takes

second sample from her tumour Lacks treated with radium but condition

worsens

Re-admitted on Aug 8, dies Oct 4, aged 31

autopsy shows widespread metastases

buried without tombstone in family cemetery in Lackstown, Virginia.

HeLa cellsLacks’ cells propagated by George

Gey No permission or consent as, by US

law, tissues or cells taken from patients do not belong to them

First human cell line, named HeLa, supposedly after Helen Lane or Helen Larson to preserve anonymity

Gey freely donated cells to scientific community: used to test first polio vaccine in the 1950s widely used for research on cancer,

infection, cell biology, toxicology etc in > 60,000 scientific papers (>300 new papers per month)

HeLa cells Original HeLa cells were mixed population

from biopsy, subsequently cloned in several labs strains of HeLa cells continue to evolve while grown in

cell culture total number of HeLa cells now far exceeds total number

of cells in Lacks' body HeLa cells grow like weed to contaminate many other

cell lines: coomon cause of scientific error and embarrassment

HeLa Genome is different from Lacks Genome HPV18 integration HeLa cells have modal chromosome number of 82, with four

copies of chromosome 12 and three copies of chromosomes 6, 8, and 17

American evolutionary biologist Leigh Van Valen claimed HeLa represents new species, Helacyton gartleri, based on : Chromosomal incompatibility of HeLa cells with humans Adaptation to novel ecological niche (cell culture) Immortal and expand beyond desire of human cultivators

Infectious cancers

Canine transmissible venereal tumor infectious cancer in dogs and other

canids caused by an immortal cell line

Tolerated by immune system because does not express MHC

Devil facial tumour disease infectious cancer in the Tasmanian

devil caused by an immortal cell line

Tolerated by immune system because Devils all have functionally identical MHC

Likely to cause extinction of Tasmanian Devils in the wild

Summary

Cancers present a microcosm of evolution, illustrating: Descent with modification Branching Evolution Natural Selection Artificial Selection

Various answers to Why Cancer?Similar principles may govern genome evolution

at species, population and cellular levelCancers and the birth and death of the soma and

the species

When we no longer look at an organic being as a savage looks at a ship, as something wholly beyond his comprehension; when we regard every production of nature as one which has had a long history; when we contemplate every complex structure and instinct as the summing up of many contrivances, each useful to the possessor, in the same way as any great mechanical invention is the summing up of the labour, the experience, the reason, and even the blunders of numerous workmen; when we thus view each organic being, how far more interesting—I speak from experience—does the study of natural history become!

Charles Darwin, Origin of Species, 1859

http://www.ncbi.nlm.nih.gov/pubmed/17301845,16701433,20615949,19956175,19360079,17989699,20877357,18723673,20359535,959840,15613288